Protection of young children from influenza through universal vaccination

Abstract

Influenza is a very common disease among infants and young children, with a considerable clinical and socioeconomic impact. A significant number of health authorities presently recommend universal influenza vaccination for the pediatric population, but a large number of European health authorities is still reluctant to include influenza vaccination in their national vaccination programs. The reasons for this reluctance include the fact that the protection offered by the currently available vaccines is considered poor. This review shows that although future research could lead to an increase in the immunogenicity and potential efficacy of influenza vaccines, the available vaccines, even with their limits, assure sufficient protection in most subjects aged ≥ 6 months, thus reducing the total burden of influenza in young children and justifying the recommendation for the universal vaccination of the whole pediatric population. For younger subjects, the vaccination of their mother during pregnancy represents an efficacious strategy.

Keywords:

• Adjuvants
• children
• influenza
• influenza prevention
• influenza vaccine
• live attenuated influenza vaccine
• pregnancy
• quadrivalent influenza vaccine
• trivalent influenza vaccine

Introduction

Influenza is a very common disease among infants and young children: attack rates range from 23% to 48% during interpandemic years and are significantly higher during pandemics.¹ This is presumed to reflect both immunological naivetè and immaturity, together with several other factors, including day-care attendance, which renders the young subject more susceptible to respiratory infections.² The severity of influenza and the incidence of related complications have long been considered to be more common in children who are at risk because of underlying chronic severe disease.³ However, recently collected data show that healthy children, particularly those younger than 2 y of age, can also suffer from severe influenza or from bacterial complications, such as otitis media and pneumonia.⁴ The risk of influenza-associated hospitalisation in these subjects has been found to be greater than the risk of hospitalisation in previously recognized high-risk groups, such as older adults.⁴ Finally, it has been reported that among healthy children, the annual number of influenza-related deaths is not different from that recorded in children with chronic disease.³ In the USA, during the 2013–2014 influenza season, 47% of pediatric deaths occurred in children with no high-risk underlying medical condition, and recent preliminary observations indicated a high number of children who required admission to the intensive care unit (ICU).³

Pediatric influenza has considerable clinical and socioeconomic impacts. During epidemic seasons up to 30% of children suffer from this disease.⁵ Several younger patients are hospitalized and, unfortunately, some of them can die.^3,5 Impact on families, medical system and society is enormous even because infected children, who shed the virus in greater amounts and for longer period than adults, are the main cause of the diffusion of the disease in the community.⁶ Global consideration of all these problems explains why some health authorities presently recommend universal influenza vaccination for all of the pediatric population, though with differences in the age limits of administration. In the USA, Austria, Estonia and Slovakia, official recommendations include all children aged 6 months − 18 years;³ in Canada, Latvia, Slovenia, Finland and a number of Latin American and Asian countries, only subjects aged 6 months – 3 y are included.⁷ Moreover, in the UK, a universal immunisation program for children aged 4–11 y was initiated in the 2013/14 influenza season.^8,9

Unfortunately, the majority of European health authorities are still reluctant to include influenza vaccination in their national vaccination programs, and they limit recommendations to the administration of influenza vaccine to high-risk subjects.¹⁰ In these countries, influenza in healthy subjects is generally seen as a mild disease that does not require any effort for systematic prevention. Moreover, the protection offered by the currently available vaccines is considered quite poor because the immunogenicity of the traditional trivalent inactivated influenza vaccines (TIVs) in children of the first years of life is lower than that usually measured in older children and adults, thus suggesting very limited protection. Consequently, vaccination of healthy children is not recommended.¹⁰ However, as previously reported, influenza can be a severe disease in children.^3,4 Moreover, the available vaccines, despite being less immunogenic in younger children, confer protection in a relevant number of cases, even when administered to very young infants.³ However, the socioeconomic impact of pediatric influenza is not always precisely evaluated and included in the final calculation of the disease's costs. Divergent results may be explained by evaluated perspective (e.g., societal and/or health care provider), data behind the models that may be quite inaccurate, different health care setting and the definition of diseases caused by influenza viruses. All of these factors can lead to underestimation of the importance of pediatric influenza and to incorrect conclusions about its prevention using the available vaccines.¹¹ On the other hand, despite differences among seasons, it has been demonstrated that in scenarios where herd protection has been included in such estimates, a program of influenza vaccination of healthy children has been shown to likely be cost-effective.¹² The aims of this review are to discuss methods for increasing the immunogenicity of influenza vaccines and to analyze how to increase the protection of young children against influenza.

Methods for Increasing the Immunogenicity of Inactivated Influenza Vaccines

To increase the immune response of children to inactivated vaccines, a number of measures that have been tested and found to be effective in adults and in the elderly have been studied in children. The use of adjuvanted vaccines, intradermal (ID) injection, the administration of an increased dose of antigens and the live attenuated influenza vaccine (LAIV) have been evaluated in controlled clinical trials, with good results. Moreover, the possibility of protecting young children through the use of a quadrivalent influenza vaccine (QIV) has been evaluated. None of these measures has been definitively accepted because of the fear of an increased risk of adverse events and because in some instances, data regarding immunogenicity and/or clinical efficacy are lacking or are not completely convincing. However, the preliminary data are very interesting in some cases and suggest that some of these measures must be further developed if the problem of the poor protection of young infants is to be solved.

Adjuvanted vaccines

The addition of adjuvants was the first method used to improve TIVs and has been the most widely studied.¹³ None of the licensed influenza vaccines are adjuvanted with aluminum salts, which are used to increase the immune response to some other vaccines. Virosomes and oil-in-water emulsions (such as MF59 and AS03) are adjuvants that are licensed in Europe, but although the former can be used in subjects of all ages, the latter cannot be administered to children if other vaccines are available.¹³

An AS03-adjuvanted vaccine specifically prepared to address the most recent influenza pandemic has been evaluated in clinical trials involving children of any age.^14,15 It was found to be significantly immunogenic, even after a single dose, and was able to confer protection for an entire year after its administration. However, the use of this vaccine was associated with an increased incidence of adverse events. For instance, in infants and toddlers, despite presenting an antigen content lower than that used in traditional influenza vaccines, the administration of a first dose was followed by pain at the injection site in 35.6% of cases, and the incidence of fever was 20.2%. The frequency of all of the adverse events increased after the second dose, reaching levels greater than 40%.¹⁶ Moreover, an increased risk of the development of narcolepsy in some European countries was clearly documented, which could explain why no further studies regarding the use of the AS03-adjuvanted influenza vaccine in healthy children have been performed thus far. ¹⁷ After extensive review, the European Medicines Agency confirmed the existence of this association, which has since been detected in England, Ireland, France, and Norway.¹⁸ Although further studies are needed to determine whether this observation exists in other populations and to elucidate potential underlying immunological mechanism, this finding has seriously damaged the reputation of influenza vaccines in children.

On the other hand, several studies conducted in children between 6 and 59 months of age have been carried out using an MF59-adjuvanted vaccine (MF59-TIV)^19-29 and a virosomal adjuvanted vaccine (VA-TIV), ^30-34 with good results.

MF59 is a low oil-in-water emulsion of microvescicles of squalene, a natural substance largely present in nature that in humans is involved in the synthesis of cholesterol and is a component of cell membranes and of sebaceous gland secretions.¹⁹ The emulsion is composed of 5% v/v squalene, 0.5 v/v polysorbate 80 (Tween 80) and 0.5% v/v sorbitan trioleate (Span 85), emulsified under high pressure conditions in a microfluidizer and transformed in small uniform droplets. Recent studies have clarified that MF59 activates, the migration of a great number of immune cells to the site of injection from the blood stream through the production of a mixture of cytokines, chemokines and other factors by muscular tissue-resident cells.²⁰ This increases the interaction between antigen presenting cells and vaccine antigens leading to a more efficient transport of vaccine antigens to the lymph nodes, which results in better T cell priming. Moreover, it was found that MF59 may enhance the immune response evoked by MF59-TIV.²¹ In open and controlled studies carried out in the elderly and adult patients with chronic underlying diseases, this vaccine was found significantly superior than the conventional TIV because able to induce higher geometric mean titers (GMT) and higher seroconversion and seroprotection rates. Interestingly, it was reported that seroprotection and seroconversion rates remained very high even in subjects without any immunity against the viral strains included in the administered vaccine²² and the addition of MF59 could protect the immunized subjects against drifted influenza strains. Similar results have been obtained in younger children in 2 preliminary studies: MF59-TIV was shown to be not only more immunogenic than conventional TIVs but also capable of inducing significantly greater cross-reactivity, at least against mismatched A/H3N2 and A/H1N1 strains.^23,24 More recently, further pediatric studies have confirmed these positive results. Nolan et al. compared the immunogenicity, reactogenicity and safety of MF59-TIV with 2 other TIVs: TIV-1, the non-adjuvanted version of MF59-TIV, and TIV-2, a split virion vaccine.²⁵ A total of 6,078 previously unprimed children received 2 doses of MF59-TIV 4 weeks apart. Approximately one month after the second vaccination, the MF59-TIV group showed significantly higher GMTs and seroconversion rates than the TIV-1 or TIV-2 group against all homologous and heterologous strains. This difference was enhanced when evaluation was performed considering antibody titres ≥110. Moreover, the adjuvanted vaccine elicited a faster, more persistent antibody response, leading to significantly higher titres after 6 months than in either TIV group. MF59-TIV was more reactogenic than TIV-1 and TIV-2, but the rates of severe adverse events were very low for all 3 vaccines.

Zedda et al. evaluated the antibody and cell-mediated responses to TIV or to MF59-TIV in previously non-vaccinated children between 6 and 35 months of age.²⁶ They reported that MF59-TIV was well tolerated and induced higher titres of HI antibodies that are able to recognize heterovariant influenza virus strains than TIV. The presence of the MF59 adjuvant induced greater expansion of vaccine-specific CD4 T cells. Interestingly, the MF59 adjuvant did not modify the cytokine profile of the elicited T cells, which was characterized by the production of interleukin (IL)-2 and tumor necrosis factor (TNF)-α, and did not bias the response toward either Th1 or Th2.

Greater immunogenicity of MF59-adjuvanted vaccines was also demonstrated when pandemic influenza preparations were tested in both older and younger children.²⁷ Regarding younger children, in children aged 6–35 months, Knuf et al. were able to demonstrate that the addition of MF59 to a pandemic influenza antigen permitted reduction of the antigen content while promoting significant long-term antibody persistence with a satisfactory safety profile.²⁸ These authors enrolled children at 6–11 months and 12–35 months of age, who received vaccine formulations containing 3.75 μg of antigen with a half standard dose of MF59, or 7.5 μg of antigen with a standard dose of MF59, or a traditional TIV containing 15 μg of antigen (only in children aged 12–35 months). The participants were administered 2 primary vaccine doses 3 weeks apart, followed by one booster dose of MF59-adjuvanted seasonal influenza vaccine one year later. Assessment of the immune response showed that all of vaccine formulations were highly immunogenic. Finally, it was reported that an MF59-adjuvanted pandemic vaccine could also induce a protective antibody response in children aged 6–36 months who had been born prematurely at ≤ 32 weeks of gestation.²⁹

Virosomes are reconstituted viral envelopes, including membrane lipids and viral spike glycoproteins, but devoid of viral genetic material.³⁰ They are biocompatible, biodegradable, nontoxic, and non-autoimmunogenic, and can serve as vehicle for delivery of viral antigens. In case of influenza vaccine, viral surface antigens glycoprotein HA and neuraminidase are attached. Because virosomes display viral envelope glycoproteins, which in their native conformation stimulate immune system through interaction with antigen presenting cells and B lymphocytes,³¹ virosomal-adjuvanted preparations evoke a more significant immune response, similar to that induced by wild influenza viruses and significantly higher than that due to the traditional inactivated vaccine. This was repeatedly found in studies carried out in healthy humans of any age and in immunocompromised subjects.³²

Data collected in children have shown that in comparison with traditional TIV, VA-TIV is able to evoke a stronger antibody response, at least for some antigens. In particular, Kanra et al. reported that in unprimed children, the seroconversion and seroprotection rates related to the A/H3N2 influenza virus were significantly higher (p = 0 .02 and p = 0.03, respectively) for VA-TIV (88.8% and 88.8%, respectively) than for TIV (77.5% and 78.3%, respectively).³³ Finally, in a recent study in which both the use of an adjuvant and an increase in the amount of antigen were evaluated, it was found that in unprimed children aged 6–35 months, the administration of a single dose of VA-TIV containing the same amount of antigen usually employed in primed subjects could evoke an immune response that satisfied the EMA/CHMP criteria for yearly vaccine licensing for all 3 vaccine strains.³⁴ Furthermore, immunogenicity was maintained 6 months after the first vaccination. Adverse events were mild, and the vaccine was well tolerated in all the studies with the exception of the study by Esposito et al.³⁴ in which a higher than expected frequency of fever above 39°C was evidenced.

Unfortunately, few studies on the efficacy of MF59-TIV in younger children are available, and neither an open nor a comparative study on the efficacy of VA-TIV has been carried out to date.¹³ However, the previously mentioned trials have demonstrated that the use of these vaccines is followed by a significant reduction of influenza-like illnesses in both vaccinated children and unvaccinated households, presenting significant advantages from medical, social and economic points of view.^21-34

Intradermal (ID) administration of TIV

The use of the skin for the administration of influenza vaccines derives from the knowledge that skin exhibits unique immunological and micro-vascular properties, particularly regarding its extreme richness in potent APCs, such as Langerhans cells (LCs) in the epidermis and dendritic cells (DCs) in the dermis.^35-37 In response to vaccination, the cutaneous immune system sets up complex mechanisms that mount an effector immune response allowing protection against related diseases. These mechanisms can be divided into several key steps that begin with the recognition and capture of the vaccine antigens by skin-resident antigen presenting cells or innate immune cells recruited by factors secreted by local APCs and is followed by the passive diffusion or cell transport of antigens to the secondary lymphoid organs draining the skin. Later, the antigens are processed and presented to immature CD4 and CD8 T cells. Activation of antigen-specific CD4 and CD8 T cells, clonal expansion as well as activation of specific B cells within a germinative center, migration of specific effector CD4 and CD8 T (cytotoxic T lymphocytes, CTLs) T cells and B cells (plasmocytes that secrete antibodies) toward the zone of vaccination and elimination of the vaccine antigens are the following steps.^35-37 Finally, generation of a pool of specific memory T and B cells in the secondary lymphoid organs takes place.^35-37

ID administration of influenza vaccines dates back to 1936, when Francis and Magill administered influenza vaccine via both ID and subcutaneous (SC) routes.³⁸ Over time, despite the demonstration that ID administration could evoke similar or marginally different immune response in comparison to intramuscular TIV,³⁹ the use of the skin was practically abandoned, mainly because of difficulties in injection due to the use of the Mantoux technique using a tuberculin syringe and the need of trained personal for administration. Additionally, the issues of leakage and incorrect placement of injections raise the possibility of suboptimal immune responses. Only recently, with the availability of new easy-to-use devices for injection ID administration come back in vogue. Several studies conducted in adults and the elderly have demonstrated that this technique leads to significantly better immune responses than are obtained intramuscularly and to responses that are not inferior to those obtained using an MF59-adjuvanted influenza vaccine.^40,41

Although few data have been collected in children, they appear to support the hypothesis that ID administration of TIV can also significantly increase the immune response in younger children, with an acceptable safety profile. To compare the immunogenicity and safety of different doses of ID-TIV with those evoked by a full dose of IM VA-TIV, Esposito et al. studied in 112 previously primed healthy children aged ≥ 3 y the immune response evoked by 2 different dose of each strain ( 9 μg or 15 μg) of ID-TIV and compared it with those due to a full IM dose (15 μg of each strain) of VA-TIV.⁴² They reported that whereas seroconversion and seroprotection rates and GMTs against A viral strains were quite similar in all the studied groups, against virus B, the one for which usually the immune response to the traditional TIV is the weakest, all these parameters were significantly higher (p < 0.05) in children receiving the ID administration with the highest dose. Local reactions were significantly more common among the children receiving either ID-TIV dose (p < 0.05), but systemic reactions were relatively uncommon in all 3 groups. These findings indicate that ID-TIV has an acceptable safety profile and that ID injection of the same dose usually administered by intramuscular injection can evoke a better protection against influenza in already primed children ≥ 3 y⁴² The lower dose of ID-TIV requires further evaluation to analyze the persistence of protection.

Administration of larger amounts of influenza antigens

Unprimed children, such as young children in most cases, are given 2 doses of TIV when they are vaccinated against influenza, one month apart, each of which contains half of the dose recommended for older children.³ This procedure is applied due to the fear of adverse events. However, because the immune response is strictly related to the amount of the administered antigens and TIV has been demonstrated to be safe and well tolerated, it was suggested that a possible solution to the problem of the relatively poor immune response to TIV in younger infants could be the administration of the same antigen dose used in older primed subjects for priming of the infants. On the other hand, an increase in antibody production after the administration of a larger amount of influenza virus antigens has been observed in adults.⁴³ The first study in children was carried out by Skowronski et al. who found that in naive infants aged 6–11 months, the administration of a double antigen dose evoked significantly higher antibody levels against all of the antigens included in the vaccine, hence increasing the probability of protection from infection and disease.⁴⁴ This occurred without any increase in the incidence of adverse events. The previously cited study by Esposito et al. in which a double dose of VA-TIV was used confirmed the possibility of priming young children with a double dose of influenza antigens to obtain a better immune response, without any significant increase in the risk of developing adverse events.³⁴

Quadrivalent influenza vaccine (QIV)

Since the 1980s, several studies have shown that 2 antigenically distinct lineages of B influenza viruses (Yamagata and Victoria) could co-circulate globally in varying proportions depending on the particular country and period examined.⁴⁵ Moreover, these studies have demonstrated that vaccination against the B virus of one lineage provides little cross-protection against the disease caused by the opposite lineage, and it has proven difficult to precisely predict which lineage will predominate during a given season.⁴⁵ Although less extensive than the burden caused by influenza A, the clinical and socioeconomic burden of influenza B is nonetheless substantial: influenza B preferentially affects children and young adults and has been associated with higher hospitalisation rates in children than influenza A.⁴⁵

To offer improved protection against influenza B strains of both lineages, QIVs have been licensed in the USA since 2013 and in some European countries since 2014. One of the main barriers that may have hindered the development of QIV in the past was the existence of a sufficient vaccine production capacity to enable a fourth vaccine component to be added to the vaccine without a subsequent reduction in the available vaccine doses and, hence, a reduction in vaccine coverage.⁴⁶ Recently, a number of studies have evaluated the immunogenicity and safety of QIV in children. In a phase III randomized study, inactivated QIV was compared with inactivated TIV in healthy children aged 3–17 y⁴⁷ The same QIV was assessed concurrently in 6–35-month-old children as a separate open-label group.⁴⁸ Both studies demonstrated non-inferiority against the shared strains and superior immunogenicity for the unique B strains.^47,48 Both the reactogenicity and safety of the QIV was consistent with the established profile of TIV.^47,48

There are few data on the efficacy of inactivated QIV in comparison with inactivated TIV in children.⁴⁹ The observed differences in efficacy are in direct relation to the percentage of circulating influenza B viruses that do not match the lineage chosen for the TIV. However, in seasons in which influenza B circulation is minimal or B viruses are well matched to the TIV strain, vaccination with QIV could still provide benefits to the individual by priming the immune response to both lineages of influenza B, so that subjects will enter future influenza seasons with antibodies to strains from both lineages.⁴⁹

Live Attenuated Influenza Vaccine (LAIV)

LAIV represents another effective approach for influenza prevention in the first years of life. LAIV is an intranasally administered seasonal influenza vaccine that contains the viruses suggested yearly by the WHO to be included in the composition of influenza vaccines.⁵⁰ Initially prepared with a trivalent composition, LAIV is now available in a formulation with 4 viral strains. To induce immune responses, the viruses included in LAIV infect and replicate in the mucosal cells of the nasopharynx; of note, LAIV viruses are unable to replicate in the lower respiratory tract and lungs because of the warmer temperature of these tissues.⁵⁰ In addition, the LAIV viral proteins are presented to the immune system in their native form, and thus, the immune responses induced by LAIV may be similar to those induced by natural influenza infection.

Most of studies regarding the immunogenicity, safety and tolerability of LAIV were carried out using the trivalent composition.^51,52 LAIV induces a strong immune response, with efficacy higher than that found in subjects receiving inactivated influenza vaccines.^53-56 Moreover, it elicits mucosal (nasal) IgA antibody responses and strong cell-mediated immunity responses, thus assuring long-term protection.⁵⁷ Finally, it induces relevant herd immunity⁵¹ and, considering also that the intranasal route makes LAIV more acceptable for children and allows administration by those with little training, its overall evaluation shows that LAIV is more effective than the injectable vaccines in children.⁵⁸

LAIV is the influenza vaccine that has been most widely evaluated in clinical trials specifically performed to measure the efficacy of influenza vaccines in the prevention of laboratory-confirmed influenza in children.^59-62 Subjects aged ≥ 2 y have mainly been included in these evaluations, although children between 6 and 23 months of age were also enrolled in some studies.⁶² The results demonstrated that in comparison with TIV, influenza caused by matched or mismatched strains of influenza occurred in 52.5% and 54.4% fewer LAIV recipients. Moreover, it was reported that the relative efficacy of LAIV compared with TIV against antigenically similar strains but not with that against mismatched strains of influenza virus may increase over time. Across these studies, the relative efficacy of LAIV compared with TIV ranged from 25% to 60% at 0–4 months post-vaccination and from 49% to 89% at >4–8 months post-vaccination.^59-62 The efficacy of LAIV is not influenced by age and has also been demonstrated by the lower incidence of influenza-associated complications in LAIV recipients in comparison with placebo or TIV recipients.

LAIV is generally well tolerated in children and adolescents,^59-62 and most of the associated adverse events are of mild-to-moderate severity. Runny nose is the most common solicited reactogenicity event, followed by headache and tiredness/decreased activity, globally occurring at an incidence of ≥1 % in LAIV recipients aged ≥2 years. The only relevant clinical problem associated with LAIV administration is the occurrence of asthma or wheezing.⁶³ In a large safety analysis in which healthy children aged 1–17 y were enrolled (n = 9,689), it was found that the risk of medically attended wheezing events in children aged 18–35 months was 4 times higher in LAIV than placebo recipients.⁶³ An active-comparator trial conducted on the basis of these results demonstrated a higher incidence of medically significant wheezing in children aged <24 months receiving LAIV than in those receiving TIV.⁶² Moreover, more children aged 6–11 months with a history of wheezing were hospitalised in the LAIV group than in the TIV group, and LAIV recipients of the same age exhibited a significantly higher rate of hospitalisation from any cause than TIV recipients. Based on these results, although none of the episodes of medically significant wheezing occurring in this study required treatment in an intensive care unit or with mechanical ventilation and no deaths occurred as a result of these adverse events, the trivalent formulation of LAIV was not approved for use in children <2 y of age.⁶³ In addition, the manufacturer's US prescribing information states that LAIV should not be used in asthmatic subjects or children aged <5 y with recurrent wheezing unless the benefits outweigh the risks. Moreover, the use of LAIV in subjects with severe asthma or active wheezing is not recommended. The same recommendations were maintained for the recently licensed quadrivalent vaccine.⁶⁴ Interestingly, in a prospective, multicenter, open-label, phase IV intervention study involving 11 secondary/tertiary centers in the United Kingdom, children with egg allergy (defined as a convincing clinical reaction to egg within the past 12 months and/or >95% likelihood of clinical egg allergy as per published criteria) were recruited.⁶⁵ Four hundred 3three doses were administered to 282 children with egg allergy: 41% had experienced prior anaphylaxis to egg, a physician's diagnosis of asthma/recurrent wheezing was noted in 67%, and 51% were receiving regular preventer therapy. Eight children experienced mild self-limiting symptoms, which might have been due an IgE-mediated allergic reaction. Twenty-six (9.4%) children experienced lower respiratory tract symptoms within 72 hours, including 13 with parent-reported wheeze, but none of these episodes required medical intervention beyond routine treatment. The authors concluded that in contrast to current recommendations LAIV appears to be safe for use in children with egg allergy and seems well tolerated in children with a diagnosis of asthma or recurrent wheeze.⁶⁵

Influenza Vaccine Administration to Pregnant Women

Very few data regarding the immune response to TIV in infants < 6 months are available,⁶⁶ which together with the fear of an increased risk of adverse events in younger subjects, explains why TIVs are licensed only for use in subjects ≥ 6 months. For subjects younger than 6 months, infant protection from influenza can be assured by maternal vaccination.^67,68 Administration of influenza vaccine is recommended by several health authorities for pregnant women at-risk because suffering from a severe chronic underlying disease. Moreover, considering that influenza can be a disease significantly more severe in pregnant women than in the general population leading in many cases to hospitalization and rarely to death, many health authorities suggest influenza vaccine also to otherwise healthy pregnant women.^69-72 In pregnant women, TIV appears to be safe and well tolerated. ^68,73, ⁷⁴ No harmful effects on fetuses, newborns and infants have been demonstrated to date. Moreover, TIV can evoke a significant immune response that leads to protection against influenza in a large number of wom-en.^75-82 Zaman et al. conducted a study involving more than 300 patients in Bangladesh in the 2004/2005 season and verified a reduction in the number of influenza-like illnesses in mothers by 36%, showing that 88% of vaccinated women produced protective levels of antibodies after vaccination.⁷⁵ Similar results were obtained by Thompson et al. in a later study.⁷⁶ The knowledge that IgG antibodies evidenced in the serum of pregnant woman actively cross the placenta and reach the fetus⁷⁷ and that additional IgA antibodies are transferred via breast milk⁷⁸ has suggested that influenza vaccination of pregnant woman may also protect the neonate and the young infant so reducing or eliminating the problem of the poor immunogenicity of the traditional TIV in the first months of life. Several studies have documented that vaccinating pregnant women could permit to reach significant antibody levels in neonates and younger infants, particularly when vaccine was administered between the 32nd and 36th week of gestation. Englund et al. reported that children of women that have received the vaccine during this period exhibited significantly higher levels of IgG antibodies at birth and at 2 months of age than those born to unvaccinated mothers.⁷⁹ In addition, no IgM antibodies against the vaccine antigens could be detected in cord or infant serum, and blastogenic responses to influenza A were observed in neonatal and infant lymphocytes. Benowitz et al. indicated 92% effectiveness of vaccination during pregnancy in preventing hospitalisation due to influenza in children 12 months after delivery.⁸⁰ Poehling et al. demonstrated that infants from mothers who were vaccinated during pregnancy showed a reduction of the risk of hospitalisation due to influenza by 45–48%.⁸¹ Eick et al. also found that children born to vaccinated mothers presented a reduced risk of influenza, by 41%, and the risk of hospitalisation arising from infection with influenza-like symptoms was reduced by 39%.⁸¹ In England in the 2013/14 season, the screening method was used to estimate the effectiveness of seasonal influenza vaccination during pregnancy in preventing influenza virus infection and influenza-related hospitalisation in infants under 6 months.⁶⁸ Seasonal influenza vaccination in pregnancy was 71% (95% confidence interval [CI]: 24–89%) effective in preventing infant influenza virus infection and 64% (95% CI: 6–86%) effective in preventing infant influenza hospitalisation.

The efficacy of maternal vaccination in conditioning high concentrations of specific antibodies in the serum of young infants was also demonstrated with the use of the monovalent influenza vaccine specifically prepared for the recent A/H1N1v pandemic. Puleston et al. evaluated humoral immunity in mother-infant pairs in which the mothers may or may not have received the pandemic influenza vaccine.⁸³ These authors found that at birth 80% of the babies of vaccinated mothers had protective serum antibody levels against A/H1N1v in comparison to 25–30% of those born to unvaccinated women (p < 0.001). Similar results were reported by Zuccotti et al. who found that administration of pandemic vaccine to pregnant women during the third trimester of pregnany induced protective antibody concentration in all the mothers and in 95.6% of neonates.⁸⁴ Moreover, later controls showed that all the children protected at birth remained protected at 2 months and that after 5 months 81.2% had still antibody concentration above the minimum protective level. Zuccotti et al. found that immunising pregnant women with the pandemic MF59-adjuvanted vaccine during the last trimester of pregnancy induced protective antibody titres in both maternal and newborn blood samples and that passively acquired serum antibodies persisted in most of the infants for at least 5 months.⁸⁴

However, despite all of these data, everywhere influenza vaccination coverage among pregnant women remains significantly lower than desired.⁸⁵

Future Perspectives

If the analysis of the advantages offered by the presently available influenza vaccines appears to justify the support for the universal vaccination of children against influenza among an increasing number of experts, it does not mean that traditional influenza vaccines cannot be improved and that other methods to protect infants cannot be identified. Increasing the immunogenicity of influenza vaccines without reducing their safety and tolerability could lead to addressing all of the doubts regarding the efficacy of the vaccines in young patients, thus increasing the acceptance the idea of universal influenza vaccination of infants and children of any age among experts. Moreover, much younger infants could be protected through the vaccination of pregnant women.

An increase in the immunogenicity of traditional TIV in children younger than 2 y could be obtained through several strategies, and in the next several years, there will likely be new sources of data on the possibility of protecting younger children from influenza. However, the available data indicate that some of these strategies, such as those based on the use of certain adjuvants and live attenuated viruses, cannot be employed due to the risk of adverse events. In other cases, the available data are encouraging, and results from studies that are ongoing will be soon available. In this context, the administration of the influenza vaccine to pregnant women, the use of adjuvants and the administration of increased amounts of antigens appear to be the most promising approaches, although some problems remain to be solved in all of these cases. Compliance with the recommendation suggesting the prescription of influenza vaccine to pregnant women is not satisfactory at present, and efforts must be made to increase influenza vaccination coverage in this group of subjects through educational programs addressing both women and physicians as well as through the use of an efficacious recall system. Adjuvants have been employed in few adequate efficacy studies in younger children and should be further evaluated. The administration of increased amount of antigens requires further evaluation, particularly regarding the issue of potential adverse events. Moreover, for all these strategies, data regarding the recently licensed quadrivalent vaccines must be collected. Finally, special efforts need to be made to develop a universal influenza vaccine with broad and persistent coverage against different influenza strains.

Conclusion

At present, in everyday practice, young children continue to receive influenza vaccines that are less immunogenic than desired, and vaccination coverage in pregnant women is suboptimal. Although future research could lead to increasing the immunogenicity and potential efficacy of influenza vaccines, it cannot be forgotten that the available vaccines, even with their limits, assure sufficient protection in most subjects aged ≥6 months, thus reducing the total burden of influenza in younger children and justifying the recommendation for the universal vaccination of the whole pediatric population. For younger subjects, the vaccination of their mother during pregnancy represents an efficacious strategy for the prevention of influenza and its complications, not only in the pregnant woman but also in neonates and infants aged <6 months.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Funding

This paper was supported in part by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2009).